Figure 1. Classification of the main human alternative splicing factors in function of their RNA‐binding domain composition.

Figure 2. The high versatility of single RRM interactions with RNA. (a) Structure of hnRNP A1 RRM2 in complex with single‐stranded telomeric DNA as a model of single‐stranded nucleic acid binding [ 36]; (b) Scheme of the four‐stranded β‐sheet with the position and sequences of main conserved RNP1 and RNP2 aromatic residues, shown in green. The RNP1 and RNP2 consensus sequences of RRMs are shown (X represents any amino acid); (c) Structure of SRp20 RRM in complex with the 5′‐CAUC‐3′ RNA [ 9]. In all figures, the ribbon of the RRM is shown in gray, the RNA nucleotides are yellow, and the protein side chains are green. The N, O, and P atoms are in blue, red, and orange, respectively. The N‐ and C‐terminal extensions of the RRM and 5′‐ and 3′‐end of RNA are indicated. Hydrogen bonds are represented by purple dashed lines; (d) Structure of Fox‐1 RRM in complex with the 5′‐UGCAUGU‐3′ RNA [ 11]; (e) Structure of RBMY RRM in complex with a stem–loop RNA capped by a 5′‐CACAA‐3′ pentaloop [ 14]. The figures were generated by the program MOLMOL [ 64]. (f) Structure of Tra2‐β1 RRM in complex with the 5′‐AAGAAC‐3′ RNA [ 16]. The N‐ and C‐terminal regions of the RRM are indicated in red. The figures were generated by the program MOLMOL [ 67]. This figure is available online www.wiley‐vch.de/home/splicing

Figure 3. Structures illustrating RRM–RNA and RRM–peptide interactions. (a) Structure of PTB RRM3 in complex with the 5′‐CUCUCU‐3′ RNA [ 19]. The β4‐strand, the β4/β5 loop and the additional β5‐strand of RRM3, which are involved in the RRM–RNA interaction are shown in red; (b) Structure of U2AF65 RRM1 in complex with U‐tract RNA [ 21]; (c) Structure of HuD RRM1 and RRM2 in complex with the 5′‐UAUUUAUUU‐3′ RNA [ 30]; (d) Structure of the CUG‐BP1 RRM3 in complex with the 5′‐UGUGUG‐3′ RNA sequence [ 31]; (e) Structure of SPF45 UHM (in gray) in complex with the SF3b155 ULM (aa 333 to 342, in blue) [ 40]; (f) Structure of PTB RRM2 (in gray) in complex with the Raver1 peptide (in blue) [ 41] and RNA (in yellow) [ 19]. The color schemes are as used in Figure 2. This figure is available online www.wiley‐vch.de/home/splicing.

Figure 4. Structures of zinc fingers and KH domains from splicing factors in complex with RNA. (a) Crystal structure of MBNL1 ZnF3 bound to the 5′‐GC‐3′ RNA sequence [ 49]; (b) Crystal structure of ZRANB2 ZnF in complex with the 5′‐GGU‐3′ RNA sequence [ 52]. The zinc atom and water molecules are represented by black and red spheres, respectively; (c) Crystal structure of Nova2 KH3 bound to the 5′‐UCAC‐3′ RNA sequence [ 57]; (d) NMR structure of SF1 KH domain bound to the 5′‐UAAC‐3′ RNA sequence [ 63]. The color schemes are as used in Figure 2. This figure is available online www.wiley‐vch.de/home/splicing

Figure 5. Splicing repression models by RNA looping. Models are based on the structures of the MBNL1 zinc fingers 3 + 4 [ 49], the PTB RRM3 + RRM4 [ 19], and the hnRNP A1 RRM1 + RRM2 dimer [ 36] bound to RNA. These proteins repress splicing by looping out cis‐acting elements essential for splicing, the pyrimidine‐rich sequence located at the 3′ splice site, as proposed by Teplova and Patel [ 49] for MBNL1, short alternative exon as proposed by Allain and coworkers [ 19] for PTB, and long alternative‐exons as proposed by Blanchette and Chabot [ 47] for hnRNP A1. This figure is available online www.wiley‐vch.de/home/splicing